The action of drugs is based on the presence of an active principle, a therapeutically useful substance. As a rule, the active principle should be mixed with other substances, which may be therapeutically active itself or are needed as adjuvants for the manufacture of a proper dosage form. With pharmaceutical operations in which powders are involved, it is important that the powder has good flow properties. Many therapeutically useful compounds, however, cannot easily be processed to dosage forms, particularly tablets or capsules, because they have an inherent unsatisfactory flow behaviour. Therefore, according to well established pharmaceutical practice, before tableting, those substances are first converted into a granulate which possesses the desired flow properties. The present invention involves wet granulation, where the active principle is mixed with a granulation liquid, which often is water and where special granulation adjuvants may be added. According to well known procedures, a wet mass is passed through a sieve grit, dried, milled and sieved. The thus resulting granulate may be used e.g. as ingredient in a tableting mixture, but when capsules are chosen as the dosage form the granulate can be used as such.
In order to lend the granules a solid consistency, according to standard practice, a wet binding substance (wet binder) should be added to the granulation mixture, especially when the granulate should contain a relatively large amount of active principle. Further information on this can be found e.g. in H. A. Lieberman and L. Lachran, Pharmaceutical Dosage Forms (1980), Vol. I, pp 113-116 ("Wet granulation") or in L. Lachman, H. A. Lieberman and J. L. Kanig, The Theory and Practice of Industrial Pharmacy, 3rd Ed., pp 320-324 ("Wet Granulation"). Examples of wet binders are acacia gum, gelatin, polyvinylpyrrolidone, starch (paste and pre-gelatinized), sodium alginate and alginate derivatives, sorbitol, glucose and other sugars, tragacanth and soluble celluloses like methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and hydroxypropylcellulose. Wet binders are usually applied in a granulation mixture in amounts of 1-10 wt % with respect to the active principle. Although the use of a wet binding substance for granulation is considered necessary to obtain a good granulate, it has appeared that tablets prepared from such granulates show a poor disintegration behaviour when immersed in water. This may be a disadvantage from the biological absorption viewpoint. The therapeutically useful substance is released from fast disintegrating tablets in a very short time, with the effect that the absorption and the therapeutic action begins earlier and higher initial drug concentrations in the body are attained.
The aim of the present invention is to provide a good quality granulate which, although containing a relatively large amount of active substance, may be further processed to solid tablets having a satisfactory disintegration behaviour.